[R35] Mapping the Structural Basis for Mechanistic Diversity in Metalloenzyme Superfamilies
Ente: National Institute of General Medical Sciences
Scadenza: 2031-02-28
Importo max: 566.332 EUR
Paese: US
Descrizione
Project summary/abstract
Biomolecule interactions with transition metals are both extraordinarily selective and chemically powerful.
Metalloproteins are critical as both important drug targets and useful reagents for various practical applications.
To understand how metalloproteins evolve and adapt to use different metals (or none at all) when trace elements
are scarce, or to elucidate how new enzyme activities arise in a given structural scaffold, members of large
metalloprotein superfamilies that either share common cofactors or biological functions are studied. In a certain
transition-metal driven essential biological transformation in DNA biosynthesis, divergent trace elements can be
used for reaction initiation. Discovery of novel metal or radical cofactors used for these processes, and their
mechanisms of assembly and deployment, will enable novel routes of enzyme inhibition in bacterial pathogens.
In a second project, structures and reaction mechanisms in two different metalloenzyme superfamilies relevant
to biocatalysis will be evaluated. These systems use common cofactors and reaction intermediates to catalyze
divergent reaction outcomes, controlled by structural features of each enzyme. A deep understanding of the
structural basis for mechanistic diversity will facilitate use of these enzymes in chemical synthesis applications.
Finally, a third project focuses on understanding how metalloenzymes acquire their metallocofactors using
periplasmic lanthanide trafficking proteins as a test case. These pathways represent a challenging molecular
recognition problem, given the similarity in size and charge of ions in the lanthanide series. A deeper
understanding of the structures of these metal-binding proteins could help understand how other biologically
relevant metals are trafficked and sorted. Our comparative approach, driven by bioinformatics, structural studies,
and collaborations with experts in protein functional and mechanistic characterization, provides detailed and
testable hypotheses about the means by which distinct chemical reactions are accomplished. It has also resulted
in discovery of entirely new families of metalloproteins and novel ways to control their activities and properties.
Going forward, the goal is to advance this comparative approach to study metalloprotein function in more
complex environments, such as within multiprotein complexes, allowing maximal leverage of fundamental
structure-function insights in practical applications including evolution of biocatalysts, design of inhibitors as
novel antibiotics, and development of protein reagents for rare-earth extraction.
Istituzione: PENNSYLVANIA STATE UNIVERSITY, THE
PI: Amie K Boal
Progetto: 2R35GM119707-11
Settori: National Institute of General Medical Sciences
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